Note that nesiritide was not associated with a worsening of mortality and renal function suggested from previous studies.

CHICAGO -- Treating acute decompensated heart failure gains little from the addition of nesiritide (Natrecor), although the drug isn't dangerous, according to results of a large international randomized trial.

The trial of more than 7,000 patients found that nesiritide had no significant impact on 30-day mortality from any cause or heart failure rehospitalization compared with placebo when added to standard therapy (9.4% versus 10.1%, P=0.31), Robert M. Califf, MD, of Duke University, and colleagues found.

The ASCEND-HF trial did show a modest reduction in dyspnea but without meeting prespecified statistical significance criteria, they reported at a press conference here at the annual American Heart Association meeting.

However, the study didn't confirm the worsening of mortality and renal function suggested previously, Califf pointed out a press conference in advance of presentation at a late-breaking clinical trial session.

Clinicians will have to decide if the "very modest effect" of nesiritide is worthwhile but don't need to refrain from use because of concern about risk, Clyde Yancy, MD, of Baylor University Medical Center in Dallas and immediate past president of the AHA, agreed at the press conference.

Nesiritide enjoyed a meteoric rise in acute decompensated heat failure after approval in 2001, based largely on its effects on dyspnea -- but then had a similarly spectacular fall around 2005, after meta-analyses suggested elevated mortality and renal problems, leading an independent panel to recommend restricting use to inpatient cases.

Although the evidence for harm in those meta-analyses conflicted with the prospective ASCEND-HF data, which Califf ascribed to inadequate data from the smaller pooled studies, he noted that it "may have done society a favor by drawing attention to the fact that we needed more data."

When the ASCEND-HF data were added to the studies previously reviewed in the meta-analyses, the combined odds ratio for 30-day mortality was 1.00 for nesiritide, Califf pointed out.

But the dyspnea benefit of the drug was likely also initially overestimated initially, he noted.

In the original trial, other therapies were withheld for the first three hours, Califf explained, whereas in ASCEND-HF nesiritide was added to standard medical therapy, which included prerandomization treatment with a loop diuretic for about 95% of patients and a vasodilator in 14% to 15%.

The pharmacologic care of patients was excellent in ASCEND-HF, much better than current clinical practice, he commented.

The trial included 7,141 patients recruited in 30 countries and randomized within 24 hours of starting intravenous treatment for acute decompensated heart failure. Patients were assigned either to double-blind placebo or to nesiritide given as an intravenous bolus of 2 µg/kg, followed by continuous intravenous infusion at 0.1 µg/kg for up to seven days.

Patients also got usual care at their treating-physician's discretion.

Neither of the coprimary endpoints showed significant benefit with nesiritide compared with placebo.

For the 30-day rate of death or heart failure rehospitalization, the hazard ratio was 0.93 (95% CI 0.80 to 1.08) with similar lack of difference in either component.

For dyspnea at six hours, the proportion with marked or moderate reduction in symptoms was 44.5% versus 42.1% (P=0.030). At 24 hours, it was 68.2% versus 66.1% (P=0.007). Neither result was significant at the P≤0.005 level set in the trial, since the statistical power had to be split between two coprimary endpoints.

Although these findings may not be encouraging for U.S. practice, Califf noted that part way through the trial European regulators announced that -- in their view -- the dyspnea endpoint was the primary endpoint and the hospitalization part of the trial wouldn't count.

"So by the European regulatory claim, this actually does meet statistical significance," he said at the press conference.

For renal safety, the proportion of patients with more than a 25% decrease in estimated glomerular filtration rate (GFR) any time through 30 days was 31.4% with nesiritide versus 29.5% with placebo (P=0.11). Creatinine values did not rise significantly compared with placebo either.

As expected, though, hypotension was significantly more common with nesiritide (P<0.001).

Whether blood pressure measurements tipped physicians off to which agent patients were on was a question raised by study discussant Eugene Braunwald, MD, of Brigham and Women's Hospital in Boston, who led the independent committee that recommended the trial.

Another question is whether physicians in real-world practice are likely to give nesiritide on top of another vasodilator as was often the case for patients in the study -- those patients were given open-label vasodilators prior to randomization, he noted at the press conference.

He congratulated Scios, the maker of nesiritide, on being willing to subject its approved drug to this kind of scrutiny in clinical trials.

"It was a disappointment, but we need to know the facts," Elliott Antman, MD, of Harvard and Brigham and Women's Hospital in Boston, told MedPage Today. Antman was not involved in the study.

The study was sponsored by Scios, a division of Johnson & Johnson.

Califf reported conflicts of interest with Johnson & Johnson.

Braunwald reported having received research support from Johnson & Johnson and being on the scientific advisory board for Cardiorentis.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.